Epidermal Growth Factor Receptor Polymorphisms Research Articles

Investigating the importance of EGFR (− 216G/T), Exo1 (K589E) and LEP (− 2548G/A) gene polymorphisms with risk of lung cancer as potential diagnostic biomarker in Iranian population

BackgroundIn Iran, lung cancer is the third most common type of cancer and its prevalence is increasing rapidly. Identification informative genetic polymorphisms in cancer causing genes including epidermal growth factor receptor (EGFR) as key gene in control of cellular proliferation via intrinsic tyrosine/kinase activity, exonuclease 1 (EXO1) as one of the upregulated gene in different human malignancies and leptin (LEP) participate in carcinogenesis in lung cancer appears to be used as potential genetic markers for predicting lung cancer risk. There is no study about investigate association of the EGFR (− 216G/T), Exo1 (K589E) and LEP (− 2548G/A) gene polymorphisms with risk of lung cancer in Iranian population. The aim of this study was investigating the association of EGFR (− 216G/T), Exo1 (K589E) and LEP (− 2548G/A) gene polymorphisms with risk of lung cancer as a potentially diagnostic biomarker in Iranian population.MethodsIn this case–control study, A total of 100 patients with lung cancer and 100 age and gender-matched healthy controls were recruited into this study and the association between EGFR (− 216G/T), Exo1 (K589E) and LEP (− 2548G/A) gene polymorphisms with the risk of lung cancer was investigated by using PCR–RFLP technique and bioinformatics approach.ResultsThe rs712829 of EGFR gene show that a significant statistical difference between G allele and risk of lung cancer (P = 0.001, OR = 2.976, CI = 95%, 1.557–5.691), in contrast, the T allele and TT genotype show a protective role against the risk of lung cancer. Result of in silico analysis indicated that the rs712829 alter splicing and promoter regulation of EGFR gene and associated with the risk of lung cancer. PCR–RFLP result for rs1047840 of Exo1 gene showed that the AA genotype and A allele of this polymorphism associated with risk of lung cancer, whereas the GG genotype show a protective effect against the risk of lung cancer (P = 0.004, OR = 5.391, CI = 95%, 1.690–17.200). On the other hand, in silico analysis showed that the existence of rs1047840 in Exo1 gene influence lung cancer susceptibility. For rs7799039 of LEP gene, PCR–RFLP analysis showed that, there is no significant association between this polymorphism and the risk of lung cancer.ConclusionThe rs712829 of EGFR gene and rs1047840 of Exo1 are associated with risk of lung cancer among Iranian population and can be used as a potentially candidate biomarker for early detection and primary prevention.

Prognostic implications of the EGFR polymorphism rs763317 and clinical variables among young Chinese lung cancer population.

The 5-year survival rate for patients with lung cancer, the world's second most frequent malignant tumor, is less than 20%, and its prognosis cannot be clearly predicted. Our aim was to analyze the epidermal growth factor receptor (EGFR) rs763317 (G>A) single nucleotide polymorphism and its association with prognosis in Chinese Han lung cancer patients. 839 patients with primary lung cancer were recruited, and genomic DNA was extracted and genotyped by SNPscan. Kaplan-Meier technique and multivariate Cox proportional hazards model were used to analyze the association between prognosis and EGFR polymorphism rs763317. A significant association after stratification by age, significantly increased lung cancer risk was associated with the AA homozygous genotype of rs763317 (adjusted hazard ratio = 2.53, 95% CI: 1.31-4.88, p=0.005), and conferred a poor survival for lung cancer patients (MST: median survival time: 13.6 months) compared with GG genotype (MST: 41.5 months), and in the recessive model AA genotype (AA vs. GG + GA; adjusted hazard ratio = 2.57, 95% CI: 1.34-4.93, p=0.004) who were young (<60 years) had a significantly increased risk of death. The EGFR polymorphism rs763617 might serve as a significant genetic marker for predicting the prognosis of lung cancer.

Side effects of tyrosine kinase inhibitors therapy in patients with non-small cell lung cancer and associations with EGFR polymorphisms: A systematic review and meta-analysis.

Rash and diarrhea are common side effects of tyrosine kinase inhibitor (TKI) therapy administered to patients with non-small cell lung cancer (NSCLC). The polymorphisms of the epidermal growth factor receptor (EGFR) gene may be a potential predictor of these side effects. The aim of the present meta-analysis was to examine the association of EGFR polymorphisms and TKI-associated toxicities. Electronic databases (PubMed, Scopus and ISI Web of Science) were searched for relevant studies. According to the inclusion and exclusion criteria, a search of the databases identified 4,918 results, among which 6 clinical trials were obtained with 1,318 patients with NSCLC. A total of 9 EGFR single nucleotide polymorphisms (SNPs) associated with TKI toxicity were identified including, rs11568315, rs712829, rs712830, rs2227983, rs2075102, rs2293347, rs11977388, rs4947492 and rs884225. The data associated with skin toxicity from rs11568315, rs712829 and rs712830 were analyzed in the present meta-analysis. Data from rs11568315 were also analyzed in relation to diarrhea. Among all the examined SNPs, statistically significant results were obtained under the dominant genetic model for CA repeats in rs11568315 (SS vs. SL+LL) with skin toxicity. The long CA repeat (SL+LL) carriers were more likely to experience skin toxicity associated with TKIs (P=0.005). By contrast, there was no significant result for diarrhea (P=0.661) under dominant genetic model for CA repeats.

Epidermal Growth Factor Receptor (EGFR) Gene Polymorphism May be a Modifier for Cadmium Kidney Toxicity.

The results of many studies indicate that cadmium (Cd) exposure is harmful to humans, with the proximal tubule of the kidney being the main target of Cd accumulation and toxicity. Studies have also shown that Cd has the effect of activating the pathway of epidermal growth factor receptor (EGFR) signaling and cell growth. The EGFR is a family of transmembrane receptors, which are widely expressed in the human kidney. The aim of this study was to investigate the kidney function estimated glomerular filtration rate (eGFR), and its relationship with plasma Cd level and EGFR gene polymorphism. Using data from Academia Sinica Taiwan biobank, 489 subjects aged 30–70 years were analyzed. The demographic characteristics was determined from questionnaires, and biological sampling of urine and blood was determined from physical examination. Kidney function was assessed by the eGFR with CKD-EPI formula. Plasma Cd (ug/L) was measured by inductively coupled plasma mass spectrometry. A total of 97 single-nucleotide polymorphisms (SNPs) were identified in the EGFR on the Taiwan biobank chip, however 4 SNPs did not pass the quality control. Multiple regression analyses were performed to achieve the study aim. The mean (±SD) plasma Cd level of the study subjects was 0.02 (±0.008) ug/L. After adjusting for confounding variables, rs13244925 AA, rs6948867 AA, rs35891645 TT and rs6593214 AA types had higher eGFR (4.89 mL/min/1.73 m2 (p = 0.035), 5.54 mL/min/1.73 m2 (p = 0.03), 4.96 mL/min/1.73 m2 (p = 0.048) and 5.16 mL/min/1.73 m2 (p = 0.048), respectively). Plasma cadmium and rs845555 had an interactive effect on eGFR. In conclusion, EGFR polymorphisms could be modifiers of Cd kidney toxicity, in which rs13244925 AA, rs6948867 AA, rs35891645 TT and rs6593214 AA may be protective, and Cd interacting with rs845555 may affect kidney function.

The Relationship between Metabolic Syndrome and Plasma Metals Modified by EGFR and TNF-α Gene Polymorphisms

With the escalating global prevalence of metabolic syndrome (MetS), it is crucial to detect the high-risk population early and to prevent chronic diseases. Exposure to various metals has been indicated to promote MetS, but the findings were controversial, and the effect of genetic modification was not considered. Epidermal growth factor receptor (EGFR) was proposed to be involved in the pathway of metabolic disorders, and tumor necrotic factor-α (TNF-α) was regarded as an early inflammatory biomarker for MetS. This research aimed to analyze the impact of EGFR and TNF-α gene polymorphisms on the prevalence of MetS under environmental or occupational exposure to metals. We gathered data from 376 metal industrial workers and 639 non-metal workers, including physical parameters, biochemical data, and plasma concentrations of six metals. According to the genomic database of Taiwan Biobank, 23 single nucleotide polymorphisms (SNPs) on EGFR gene and 6 SNPs on TNF-α gene were incorporated in our research. We applied multivariable logistic regression to analyze the probability of MetS with various SNPs and metals. Our study revealed some susceptible and protective EGFR and TNF-α genotypes under excessive exposure to cobalt, zinc, selenium, and lead. Thus, we remind the high-risk population of taking measures to prevent MetS.

The Association of Renal Function and Plasma Metals Modified by EGFR and TNF-α Gene Polymorphisms in Metal Industrial Workers and General Population.

Exposure to metals may be associated with renal function impairment, but the effect modified by genetic polymorphisms was not considered in most studies. Epidermal growth factor receptor (EGFR) and tumor necrotic factor-α (TNF-α) play important roles in renal hemodynamics, and they have been reported to be associated with some renal diseases. The aim of our research is to explore whether genetic variations in EGFR and TNF-α have influence on renal function under exposure to various metals. This cross-sectional study consisted of 376 metal industrial workers, 396 participants of Taiwan Biobank, and 231 volunteers of health examinations. We identified 23 single nucleotide polymorphisms (SNPs) on the EGFR gene and 6 SNPs on the TNF-α gene, and we also measured their plasma concentration of cobalt, copper, zinc, selenium, arsenic, and lead. Multiple regression analysis was applied to investigate the association between various SNPs, metals, and renal function. Our results revealed some protective and susceptible genotypes under occupational or environmental exposure to metals. The individuals carrying EGFR rs2280653 GG might have declined renal function under excessive exposure to selenium, and those with EGFR rs3823585 CC, rs12671550 CC, and rs4947986 GG genotypes might be susceptible to lead nephrotoxicity. We suggest the high-risk population to prevent renal diseases.

The EGFR Polymorphism Increased the Risk of Hepatocellular Carcinoma Through the miR-3196-Dependent Approach in Chinese Han Population.

BackgroundPrevious studies have shown that epidermal growth factor receptor (EGFR) promotes cell proliferation through the PI3K-Akt-mTOR signaling pathway and participates in the occurrence and development of hepatocellular carcinoma (HCC). Here, we focused on the functional polymorphism of EGFR in the 3ʹ-untranslated region (UTR), aiming to reveal the potential mechanisms by which functional polymorphism is associated with the risk and development of HCC in the Han Chinese population.MethodsThis study was a hospital-based case-control study. A total of 600 patients were enrolled, and another 600 healthy volunteers served as controls. The miR-associated SNPs in EGFR were screened, and genotyping was performed by TaqMan allele differential analysis. In this study, genotyping, real-time PCR, cell transfection and double luciferase reporter gene were used for subsequent analysis.ResultsHBV/HCV infection instead of alcohol exposure, smoking exposure, hypertension or diabetes mellitus was associated with an increased risk of HCC. Compared with TT genotypes, TG and GG genotypes of EGFR rs884225 were significantly associated with reduced HCC risk. The stratified analysis of association between rs884225 and HCC subgroup feature reveal a highly correlation with tumor size. Furthermore, qRT-PCR confirmed that EGFR rs884225, TG and GG genotypes were more likely to bind to miR-3196 and down-regulate EGFR level in cells, thereby inhibiting cell proliferation.ConclusionThis study suggested that EGFR rs884225 is associated with a reduced risk of liver cancer and may be a developing biomarker.

The investigation of the amounts and expressions of epidermal growth factor, epidermal growth factor receptor, and epidermal growth factor receptor gene polymorphisms in acne vulgaris.

Epidermal growth factor receptor inhibitors (EGFRI) used in cancer chemotherapy cause acneiform folliculitis in 70%-100% of patients in a dose-dependent manner. Acneiform folliculitis is considered to be caused by an inflammatory process due to follicular hyperkeratosis and subsequently a set of changes both in epidermis and hair follicles as a result of epidermal growth factor receptor (EGFR) blockade. Both acne vulgaris and acneiform folliculitis due to EGFRIs show similar changes in the pilosebaceous unit. Furthermore, in both groups of patients, topical application of recombinant human epidermal growth factor (EGF) has been reported to improve the disease. In this study, it was aimed to investigate the role of EGF and EGFR amount, expression, and EGFR gene polymorphisms in the etiopathogenesis of acne vulgaris. 156 acne vulgaris patients, within 18-25years of age, who had 15 or more inflammatory acne lesions on dermatologic evaluation were included in this study. The absence of any known systemic or genetic disease or cancer and any systemic or topical treatment for the last 1month were prerequisites. In the control group, 154 volunteers in the same age range who were examined at the outpatient clinic with diagnoses of melanocytic nevus, ephelid, cherry angioma, and callus and who had no more than 3 inflammatory acne lesions were recruited. The amounts of EGF and EGFR were determined by sandwich ELISA, expressions of EGF and EGFR by reverse transcriptase polymerase chain reaction; EGFR polymorphisms were examined by restriction enzyme digestion, Sanger, and high-resolution melting methods. The patient and control groups were compared in terms of EGFR gene polymorphisms in addition to the amount and expressions of EGF and EGFR. The amount of EGF in the serum was found to be significantly higher in the acne group. (P=.0012). There was no significant difference in other parameters studied. The results of our study showed a significant increase in the amount of EGF in the acne group. Though EGF may be incriminated in the etiopathogenesis of AV, the most likely explanation about its role may be controlling inflammation from the very first stage.

Epidermal growth factor receptor rs17337023 polymorphism in hypertensive gestational diabetic women: A pilot study.

BACKGROUNDWomen with gestational diabetes mellitus have an increased risk of developing gestational hypertension, which can increase fetal and neonatal morbidity and mortality. In the past decade, single nucleotide polymorphisms in several genes have been identified as risk factors for development of gestational hypertension. The epidermal growth factor receptor activates tyrosine kinase mediated blood vessels contractility; and inflammatory cascades. Abnormalities in these mechanism are known to contribute towards hypertension. It is thus plausible that polymorphisms in the epidermal growth factor receptor gene would be associated with the development of hypertension in women with gestational diabetes.AIMTo determine whether the epidermal growth factor receptor rs17337023 SNP is associated with the occurrence of hypertension in gestational diabetic women.METHODSThis pilot case-control study was conducted at two tertiary care hospitals in Karachi, from January 2017-August 2018. Two hundred and two women at 28 week of gestation with gestational diabetes were recruited and classified into normotensive (n = 80) and hypertensive (n = 122) groups. Their blood samples were genotyped for epidermal growth factor receptor polymorphism rs17337023 using tetra-ARMS polymerase chain reaction. Descriptive analysis was applied on baseline data. Polymorphism data was analyzed for genotype and allele frequency determination using chi-squared statistics. In all cases, a P value of < 0.05 was considered significant.RESULTSSubjects were age-matched and thus no difference was observed in relation to age of the study subjects (P >0.05). Body fat percentage was significantly higher in hypertensive females as compared to normotensive subjects (35.138 ± 4.29 Case vs 25.01 ± 8.28 Control; P < 0.05). Similarly, systolic and diastolic blood pressures among groups were significantly higher in hypertensive group than the normotensive group (P < 0.05). Overall epidermal growth factor receptor rs17337023 polymorphism genotype frequency was similar in both groups, with the heterozygous AT genotype (56 in Case vs 48 in Control; P = 0. 079) showing predominance in both groups. Furthermore, the odds ratio for A allele was 1.282 (P = 0.219) and for T allele was 0.780 (P = 0.221) in this study.CONCLUSIONThis pilot study indicates that polymorphisms in rs17337023 may not be involved in the pathophysiology of gestational hypertension in gestational diabetes via inflammatory cascade mechanism. Further large-scale studies should explore polymorphism in epidermal growth factor receptor and other genes in this regard.

EGFR, SMAD7, and TGFBR2 Polymorphisms Are Associated with Colorectal Cancer in Patients with Lynch Syndrome.

Epidermal growth factor receptor (EGFR), mothers against decapentaplegic homolog 7 (SMAD7) and transforming growth factor betta (TGFB) are crucial for colorectal cancer (CRC) tumorigenesis. This study investigated whether polymorphisms in EGFR, SMAD7, and TGFB are associated with CRC risk in patients with Lynch syndrome. Genotyping was performed using Sequenom iPLEX MassArray. Association between genetic polymorphisms and CRC was assessed using a weighted Cox proportional hazard model. Patients carrying the AA genotype of EGFR rs2227983 had a significantly higher CRC risk than those carrying the G allele (HR=2.55, 95% CI=1.25-5.17). The dominant model of SMAD7 rs12953717 (CT + TT genotypes) significantly increased CRC risk (HR=2.17, 95% CI=1.12-4.16) when compared to the wild-type CC genotype. Similarly, the GG genotype of TGFBR2 rs6785358 significantly increased the risk of CRC (HR=21.1, 95% CI=5.06-88.1) compared to the AA genotype. EGFR, SMAD7, and TGFBR2 are associated with CRC risk in patients with Lynch syndrome.

The Impact of EGFR Gene Polymorphisms on the Risk of Alzheimer's Disease in a Chinese Han Population: A Case-Controlled Study.

BackgroundThe aim of this study was to investigate the association between polymorphisms of the epidermal growth factor receptor (EGFR) gene with the risk of Alzheimer’s disease (AD) in a Chinese Han population.Material/MethodsA polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to genotype 139 patients with AD and 152 healthy control individuals. The Hardy-Weinberg equilibrium (HWE) was analyzed using the chi-squared (χ2) test, and genotype and allele frequencies were compared between the two population groups, using the χ2 test. The odds ratios (ORs) and corresponding 95% confidence intervals (CI) were calculated to express the degree of risk of AD resulting from polymorphisms in the EGFR gene. Linkage disequilibrium among EGFR polymorphisms was analyzed using the Haploview bioinformatics software.ResultsThe CC genotype and C allele frequencies of rs730437 were significantly lower in patients with AD compared with the controls (P=0.037), indicating that rs730437 was associated with a reduced risk of AD (CC vs. AA: OR=0.446, 95% CI=0.207–0.960) (C vs. A: OR=0.702, 95% CI=0.502–0.980). The presence of the TT genotype of rs1468727 significantly reduced the risk of AD (P=0.003; OR=0.333, 95% CI=0.160–0.691), and T allele carriers of rs1468727 had a 0.605-fold increased risk of AD. Haplotype A-C-C was significantly correlated with an increased risk of AD (OR=1.922, 95% CI=1.130–3.269).ConclusionsIn a Han Chinese population, EGFR gene polymorphisms, rs730437 and rs1468727 and haplotype A-C-C were shown to be possible protective factors for the development of AD.

Epidermal growth factor receptor (EGFR) pathway polymorphisms as predictive markers of cetuximab toxicity in locally advanced head and neck squamous cell carcinoma (HNSCC) in a Spanish population

ObjectivesTo examine the relationship between polymorphisms of the epidermal growth factor receptor (EGFR) pathway and toxicity in head and neck squamous cell carcinoma (HNSCC) patients treated with cetuximab. Material and methodsMulticenter, retrospective, observational pilot study which included 110 patients with histologically-confirmed human papillomavirus (HPV) negative HNSCC in locally advanced stages (III-IVA-B) and who were treated with chemotherapy and radiotherapy plus cetuximab between 2003 and 2013. Genetic analyses for single nucleotide polymorphisms (SNP) in genes EGFR, CCDN1, FCGR2A, FCGR3A and KRAS-LCS6 were performed though available allelic discrimination assay and/or polymerase chain reaction-restriction fragment length polymorphism methods. ResultsAcneiform rash was observed in 55.5% of patients, dry skin in 45.5% and pruritus in 20.9%. A significant association with dry skin and global cetuximab-related toxicity was observed for the KRAS-LCS6 (rs61764370) variant (p<0.05); carriers of the G allele (genotypes TG+GG) in the dominant model were observed to have a decreased susceptibility of developing dry skin (OR=0.287 [95%CI=0.119–0.695]). Carriers of the A (GA+AA) allele for EGFR (rs2227983) showed a decreased risk of suffering from pruritus (OR=0.345 [0.124–0.958]). Similarly, KRAS (rs1801274) was related with lower global cetuximab-related toxicity (OR=0.266 [0.114–0.622]). ConclusionThis pilot study provides preliminary evidence supporting genetic variation of EGFR (rs2227983), KRAS (rs61764370) and FCGR2A (rs180127) as useful biomarkers for predicting reduced skin toxicity in HNSCC patients treated with a cetuximab-based therapy. Alternative therapeutic options should be explored for these patients.

Association analysis of polymorphisms in EGFR, HER2, ESR1 and THRA genes with coronary artery diseases

BackgroundResearch in the genetic basis of coronary artery diseases (CAD) has identified some genes and pathways associated with diseases that would not be considered to underlie conventional risk factors. Among these genes there are the EGFR (epidermal growth factor receptor) receptor family genes and the regulation factor genes (such as thyroid hormone receptor α (THRA) and estrogen receptor α (ESR1)). AimIn this study we investigated the relation between 4 polymorphisms within EGFR, HER2 (human epidermal growth factor receptor 2), ESR1 and THRA genes and CAD. Subjects and methodsThe association analysis was performed with 151 healthy individuals and 151 CAD patients documented by angiography. ResultsNo significant difference was found in the allelic and genotypic frequency distribution of the four variants studied between the control and patient groups. We have also investigated the relationship of these polymorphic sites with clinical and biochemical parameters such as smoking habit, diabetes mellitus, hypertension, dyslipidemia, CAD severity, glucose, triglyceride, total cholesterol and urea levels. The EGFR and THRA variants were associated with glycemia and triglyceride levels, respectively. Also a significant correlation was found between the ESR1 polymorphism and the levels of urea and triglyceride. ConclusionOur results suggest the absence of any significant association between the four polymorphisms analyzed and CAD risk as well as disease severity.

Effect of epidermal growth factor receptor gene polymorphisms on prognosis in glioma patients.

Previous studies suggested that single nucleotide polymorphisms (SNPs) in epidermal growth factor receptor (EGFR) are associated with risk of glioma. However, the associations between these SNPs and glioma patient prognosis have not yet been fully investigated. Therefore, the present study was aimed to evaluate the effects of EGFR polymorphisms on the glioma patient prognosis. We retrospectively evaluated 269 glioma patients and investigated associations between EGFR SNPs and patient prognosis using Cox proportional hazard models and Kaplan-Meier curves. Univariate analysis revealed that age, gross-total resection and chemotherapy were associated with the prognosis of glioma patients (p < 0.05). In addition, four EGFR SNPs (rs11506105, rs3752651, rs1468727 and rs845552) correlated with overall survival (OS) (Log-rank p = 0.011, 0.020, 0.008, and 0.009, respectively) and progression-free survival PFS (Log-rank p = 0.026, 0.024, 0.019 and 0.009, respectively). Multivariate analysis indicated that the rs11506105 G/G genotype, the rs3752651 and rs1468727 C/C genotype and the rs845552 A/A genotype correlated inversely with OS and PFS. In addition, OS among patients with the rs730437 C/C genotype (p = 0.030) was significantly lower OS than among patients with A/A genotype. These data suggest that five EGFR SNPs (rs11506105, rs3752651, rs1468727, rs845552 and rs730437) correlated with glioma patient prognosis, and should be furthered validated in studies of ethnically diverse patients.

Epidermal growth factor receptor expression in gastric tumors and its relationship with the germline polymorphisms - 216 G>T, -191 C>A, (CA) n IVS1, and R521K.

Gastric cancer (GC) is the third worldwide leading cause of cancer-related death affecting both sexes. The aberrant expression of epidermal growth factor receptor (EGFR) gene has been detected in many human epithelial malignancies and linked to advanced disease, more aggressive phenotype, and poor prognosis. To analyze the relation that the expression of EGFR in gastric tumors holds with pathological characteristics and with the germline polymorphisms -216 G>T, -191 C>A, (CA) n IVS1, and R521K. We studied 22 biopsies from gastric tumors obtained by endoscopy. EGFR expression was determined by relative quantification real-time polymerase chain reaction with the glyceraldehyde-3-phosphate dehydrogenase reference gene (as for messenger RNA [mRNA]) and by immunohistochemistry (IHC) (as for protein). EGFR germline polymorphisms were analyzed by sequencing, GeneScan, and restriction fragment length polymorphisms. EGFR mRNA expression was increased (>2-fold) in 13.6% of GC cases, decreased (<0.5-fold) in 68.2%, and normal in 18.2%; overexpression was related to well-differentiated gastric tumors, whereas underexpression was linked to moderate or poorly differentiated gastric tumors (P < 0.001). EGFR protein expression was high (IHC 2+ and 3+) in 29.4% of gastric tumors and was normal or low (score 0 to 1+) in 70.6% cases. EGFR expression, in both mRNA and protein, was not related to any EGFR polymorphism (P > 0.05). Most gastric tumors showed low EGFR expression (mRNA and protein), whereas EGFR overexpression was related to well-differentiated gastric tumors. Furthermore, germinal polymorphisms -216, -191, (CA) n IVS1, and R521K were not related to EGFR expression (mRNA or protein).

A synonymous EGFR polymorphism predicting responsiveness to anti-EGFR therapy in metastatic colorectal cancer patients.

Genetic factors are known to affect the efficiency of therapy with monoclonal antibodies (mAbs) targeting the epidermal growth factor receptor (EGFR) in patients with metastatic colorectal cancer (mCRC). At present, the only accepted molecular marker predictive of the response to anti-EGFR mAbs is the somatic mutation of KRAS and NRAS as a marker of resistance to anti-EGFR. However, only a fraction of KRAS wild-type patients benefit from that treatment. In this study, we show that the EGFR gene polymorphism rs1050171 defines, independently of RAS mutational status, a sub-population of 11% of patients with a better clinical outcome after anti-EGFR treatment. Median PFS for patients with the GG genotype was 10.17months compared to 5.37 of those with AG + AA genotypes. Taken together, our findings could be used to better define CRC populations responding to anti-EGFR therapy. Further studies in larger independent cohorts are necessary to validate the present observation that a synonymous polymorphism in EGFR gene impacts on clinical responsiveness.

Construction of possible integrated predictive index based on EGFR and ANXA3 polymorphisms for chemotherapy response in fluoropyrimidine-treated Japanese gastric cancer patients using a bioinformatic method.

BackgroundVariability in drug response between individual patients is a serious concern in medicine. To identify single-nucleotide polymorphisms (SNPs) related to drug response variability, many genome-wide association studies have been conducted.MethodsWe previously applied a knowledge-based bioinformatic approach to a pharmacogenomics study in which 119 fluoropyrimidine-treated gastric cancer patients were genotyped at 109,365 SNPs using the Illumina Human-1 BeadChip. We identified the SNP rs2293347 in the human epidermal growth factor receptor (EGFR) gene as a novel genetic factor related to chemotherapeutic response. In the present study, we reanalyzed these hypothesis-free genomic data using extended knowledge.ResultsWe identified rs2867461 in annexin A3 (ANXA3) gene as another candidate. Using logistic regression, we confirmed that the performance of the rs2867461 + rs2293347 model was superior to those of the single factor models. Furthermore, we propose a novel integrated predictive index (iEA) based on these two polymorphisms in EGFR and ANXA3. The p value for iEA was 1.47 × 10−8 by Fisher’s exact test. Recent studies showed that the mutations in EGFR is associated with high expression of dihydropyrimidine dehydrogenase, which is an inactivating and rate-limiting enzyme for fluoropyrimidine, and suggested that the combination of chemotherapy with fluoropyrimidine and EGFR-targeting agents is effective against EGFR-overexpressing gastric tumors, while ANXA3 overexpression confers resistance to tyrosine kinase inhibitors targeting the EGFR pathway.ConclusionsThese results suggest that the iEA index or a combination of polymorphisms in EGFR and ANXA3 may serve as predictive factors of drug response, and therefore could be useful for optimal selection of chemotherapy regimens.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1721-z) contains supplementary material, which is available to authorized users.

Polymorphisms in EGFR and IL28B are associated with spontaneous clearance in an HCV-infected Iranian population.

Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% of them are able to clear the virus spontaneously without any therapeutic intervention. The aim of the present study was to identify genes associated with spontaneous HCV clearance in a population of Iranian patients. We genotyped 110 single-nucleotide polymorphisms (SNPs) in 59 selected--candidate--genes in a cohort of 107 HCV-infected participants who spontaneously cleared the infection and 176 participants whose infection persisted. Three out of the 110 SNPs were found to be associated with HCV outcome (P-values<0.03). rs11506105 in EGFR (epidermal growth factor receptor gene), and rs11881222 and rs12979860 in IL28B (interferon-λ3 gene). Multivariate logistic regression of the three markers showed that the A/A genotypes in both rs11506105 (EFGR) and rs11881222 (IL28B), and the C/C genotype in rs12979860 (IL28B) are associated with HCV clearance (recessive model: odds ratio (OR)=2.06, 95% confidence interval (95% CI)=1.09-3.88, P=0.025; OR=2.09, 95% CI=1.23-3.60, P=0.007; and OR=1.95, 95% CI=1.15-3.35, P=0.014 for rs11506105, rs12979860 and rs11881222, respectively). In conclusion, EGFR and IL28B SNPs are strong independent predictive markers of spontaneous viral clearance.

Discrimination of driver and passenger mutations in epidermal growth factor receptor in cancer

Cancer is one of the most life-threatening diseases and mutations in several genes are the vital cause in tumorigenesis. Protein kinases play essential roles in cancer progression and specifically, epidermal growth factor receptor (EGFR) is an important target for cancer therapy. In this work, we have developed a method to classify single amino acid polymorphisms (SAPs) in EGFR into disease-causing (driver) and neutral (passenger) mutations using both sequence and structure based features of the mutation site by machine learning approaches. We compiled a set of 222 features and selected a set of 21 properties utilizing feature selection methods, for maximizing the prediction performance. In a set of 540 mutants, we obtained an overall classification accuracy of 67.8% with 10 fold cross validation using support vector machines. Further, the mutations have been grouped into four sets based on secondary structure and accessible surface area, which enhanced the overall classification accuracy to 80.2%, 81.9%, 77.9% and 75.1% for helix, strand, coil-buried and coil-exposed mutants, respectively. The method was tested with a blind dataset of 60 mutations, which showed an average accuracy of 85.4%. These accuracy levels are superior to other methods available in the literature for EGFR mutants, with an increase of more than 30%. Moreover, we have screened all possible single amino acid polymorphisms (SAPs) in EGFR and suggested the probable driver and passenger mutations, which would help in the development of mutation specific drugs for cancer treatment.

MTHFR C677T Polymorphism is Associated with Tumor Response to Preoperative Chemoradiotherapy: A Result Based on Previous Reports.

BackgroundPreoperative chemoradiotherapy (pRCT) followed by surgery has been widely practiced in locally advanced rectal cancer, esophageal cancer, gastric cancer and other cancers. However, the therapy also exerts some severe adverse effects and some of the patients show poor or no response. It is very important to develop biomarkers (e.g., gene polymorphisms) to identify patients who have a higher likelihood of responding to pRCT. Recently, a series of reports have investigated the association of the genetic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and epidermal growth factor receptor (EGFR) genes with the tumor response to pRCT; however, the results were inconsistent and inconclusive.Material/MethodsA systematic review and meta-analysis was performed by searching relevant studies about the association of MTHFR and EGFR polymorphisms with the tumor regression grade (TRG) in response to pRCT in databases of PubMed, EMBAS, Web of science, Chinese National Knowledge Infrastructure, and Wanfang database up to March 30, 2015. The pooled odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs) were calculated to assess the strength of the association under 5 genetic models.ResultsA total of 11 eligible articles were included in the present meta-analysis, of which 8 studies were performed in rectal cancer and 3 studies were performed in esophageal cancer. We finally included 8 included studies containing 839 cases for MTHFR C677T, 5 studies involving 634 cases for MTHFR A1298C, 3 studies containing 340 cases for EGFR G497A, and 4 studies containing 396 cases for EGFR CA repeat. The pooled analysis results indicated that MTHFR C677T might be correlated with the tumor response to pRCT under the recessive model (CC vs. CTTT) in overall analysis (OR=1.426(1.074–1.894), P=0.014), rectal cancer (OR=1.483(1.102–1.996), P=0.009), and TRG 1–2 vs. 3–5 group (OR=1.423(1.046–1.936), P=0.025), while other polymorphism including MTHFR A1298C, EGFR G497A, and EGFR CA repeat polymorphisms exerted significant association under all genetic models in overall analysis or subgroup analysis.ConclusionsMTHFR C677T might be correlated with the tumor response to pRCT. Further well-designed, larger-scale epidemiological studies are needed to validate our results.